Men and women differ in their behavior and susceptibility to disease. This project aims to understand the biological origins of sex differences in the brain and behavior, in health and disease. The novel mouse model, the four core genotypes (FCG), offers significant advantages for discriminating among several classes of biological factors that lead to sex differences in the brain, including organizational and activational effects of gonadal hormones, and direct effects of X and Y genes that are present in different numbers in the XX and XY genome. We propose to use the FCG model to investigate further sex differences in nociception and analgesia and in stress- induced changes in gastrointestinal motor function. A major goal is to develop a better understanding of direct actions of sex chromosome genes that lead to sex differences. We will investigate whether direct sex chromosome effects cause sex differences in stress-induced analgesia, in the effectiveness of kappa opioid analgesic drugs and their modulation by glutaminergic systems, in the effects of neuropathic nociception, and in effects of morphine. We will also investigate the sites and mechanisms by which sex chromosome genes lead to sex differences in neurovisceral changes underlying colonic motor responses induced by stress. The interaction of sex chromosome effects and gonadal hormone effects will be studied. We propose to identify X and Y genes that are directly responsible for the sex differences in these systems. The results will shed light on fundamental sex differences in nociception, stress, and neurovisceral responses to stress, leading to great understanding of sex-specific factors that ameliorate or exacerbate disease. PUBLIC HEALTH RELEVANCE: Men and women show significant differences in behavior and in their susceptibility to diseases of the brain. The proposed research aims to understand the biological origins of such sex differences, especially those differences that are caused by the sex differences in genomic representation of X and Y genes. Understanding the molecular basis of sex differences will shed light on factors that protect the brain from disease.